Reductions in plasma cytokine levels with weight loss improve insulin sensitivity in overweight and obese postmenopausal women

OBJECTIVE - The purpose of this study was to determine whether improvements in insulin sensitivity with weight loss are mediated by changes in inflammation in obese, postmenopausal women. RESEARCH DESIGN AND METHODS - We studied 58 sedentary, overweight, and obese (BMI 33 +/- 1 kg/m(2), means +/- SEM) postmenopausal (58 +/- 1 year) women at baseline and 37 women who completed 6 months of weight loss induced by diet and exercise. The women underwent 3-h hyperinsulinemic-euglycemic clamps (40 mU.m(-2). min(-1)) to determine glucose utilization (M). Insulin sensitivity was determined as M/l, the amount of glucose metabolized per unit of plasma insulin (I). Visceral adipose tissue (VAT) and plasma concentrations of C-reactive protein (CRP), cytokines interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha, as well as their soluble receptors, were measured. RESULTS - At baseline, insulin sensitivity, independent of adiposity, race, and aerobic fitness (M: partial r = -0.30, p = 0.03, and M/I: partial r = -0.32, P = 0.02). Weight loss resulted In significant reductions in body weight, fat mass, VAT, and fasting glucose and insulin levels (P < 0.05). Both glucose utilization and insulin sensitivity increased by 16% (P < 0.05) CRP, IL-6, and soluble TNF receptor (sTNFR)-1 concentrations decreased (P < 0.05), but concentrations of TNF-alpha, sTNFR-2, and soluble IL-6 receptor (IL-6sR) did not change. In stepwise regression models to predict changes in glucose homeostasis, changes in VAT and sTNF-R1 independently predicted changes in glucose utilization (r = -0.49 and cumulative r = -0.64, P < 0.01), while changes in VAT and IL-6 were both independent predictors of changes in insulin Sensitivity (r = -0.57, and cumulative r = -0.68, P < 0.01). CONCLUSIONS - Improvements in glucose metabolism with weight loss programs are independently associated with decreases in cytokine concentrations, suggesting that a reduction in inflammation is a potential mechanism that mediates improvements in insulin sensitivity.